Drug Flops for Delirium

Action Points

Explain that a randomized clinical trial of rivastigmine for delirium in intensive care unit patients was halted prematurely due to lack of a beneficial effect for the cholinesterase inhibitor, as well as possible increased mortality.

Note that severity of delirium and length of ICU stay were also increased in those receiving rivastigmine.

The cholinesterase inhibitor, rivastigmine, did not have any beneficial effects as an adjunct to haloperidol in critically ill patients with delirium, and it may have increased mortality, according to the results of a prematurely ended randomized controlled trial.

After just 104 of a planned 440 patients were enrolled, the trial was halted because of a nonsignificant trend toward increased mortality with rivastigmine compared with placebo (22% versus 8%, P=0.07), Arjen Slooter, MD, PhD, of the University Medical Center Utrecht in the Netherlands, and colleagues reported online in The Lancet.

The drug did not decrease the duration or severity of delirium.

Because of the lack of benefits and possible harm, "we do not recommend treatment of delirium with rivastigmine for patients in intensive care," Slooter and his colleagues wrote.

Impaired cholinergic neurotransmission is believed to be involved in the development of delirium, so cholinesterase inhibitors have been used off-label to treat the condition and have been mentioned in practice guidelines as possibly beneficial.

Rivastigmine, which is approved for Alzheimer's disease, Parkinson's disease dementia, and Lewy-body dementia, has been shown in a case series to ease delirium, but the results had not been seen in clinical trials.

In an accompanying editorial, Yoanna Skrobik, MD, of Maisonneuve Rosemont Hospital in Montreal, suggested some reasons why rivastigmine failed in the current study.

"Delirium in an elderly patient with Alzheimer's disease but who is not critically ill might be a different disease," she wrote. "Baseline cognitive function is different, as is the degree of systemic inflammation, a potential factor in psychiatric or psychological dysfunction."

In addition, she wrote, "neurohormonal transmission might vary significantly from one individual to the next, as might the response to drug treatment."

Slooter and his colleagues enrolled adult patients with delirium from six intensive care units in the Netherlands. They assigned patients to placebo or a dose of rivastigmine starting at 0.75 mL (1.5 mg rivastigmine) twice daily and escalating to 3 mL (6 mg rivastigmine) twice daily.

Patients in both groups received usual care, which included haloperidol three times daily, frequent orientation, physical therapy, and exercise.

The trial's data safety and monitoring board conducted interim analyses every three months. After the fourth analysis, the board stopped the trial because of the apparent increase in mortality with rivastigmine. After 90 days of follow-up, the numerical difference remained, although it still was not statistically significant (33% versus 22%, P=0.14).

Rivastigmine was not associated with any benefits; in fact, there was a nonsignificant trend toward a longer duration of delirium in the rivastigmine group (5 versus 3 days, P=0.06), as well as significantly greater delirium severity (P=0.004).

Patients who received rivastigmine also spent a significantly greater percentage of their days in the study in a coma (10% versus 3%) and had a longer stay in the intensive care unit (15 versus 8 days; P<0.0001 for both).

The researchers pointed out some potential concerns about the study, including the diagnosis of delirium by trial nurses and physicians, rather than by a psychiatrist, neurologist, or geriatrician, and the use of the Delirium Severity Index, which has not been externally validated.

The study was funded by ZonMw, the Dutch organization for health research and development; the Netherlands Brain Foundation; and Novartis, which supplied the study drug.

Slooter reported that he had no conflicts of interest. One of his co-authors reported receiving payment and travel expenses for presentations and attendance at committee meetings from the following professional organizations: the Netherlands Society of Psychiatry, the Netherlands Society of Intensive Care, the Health Care Inspectorate, and the Academic Medical Center, University of Amsterdam.

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